Comprehensive Overview of the Structure and Regulation of the Glucocorticoid Receptor

Glucocorticoids are among the most prescribed drugs worldwide for the treatment of numerous immune and inflammatory disorders. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. There are several GR isoforms resulting from alternative RNA splicing and translation initiation of the GR transcript. Additionally, these isoforms are all subject to several transcriptional, post-transcriptional, and post-translational modifications, all of which affect the protein's stability and/or function. In this review, we summarize recent knowledge on the distinct GR isoforms and the processes that generate them. We also review the importance of all known transcriptional, post-transcriptional, and post-translational modifications, including the regulation of GR by microRNAs. Moreover, we discuss the crucial role of the putative GR-bound DNA sequence as an allosteric ligand influencing GR structure and activity. Finally, we describe how the differential composition and distinct regulation at multiple levels of different GR species could account for the wide and diverse effects of glucocorticoids. (Endocrine Reviews 35: 671-693, 2014) I. Introduction II. Regulation of GR Gene Expression A. Genomic structure of GR B. Transcriptional control of the GR-coding gene NR3C1 C. Post-transcriptional regulation of the GR transcript III. Splice Variants and Isoforms of GR A. Alternative mRNA splicing B. Alternative translation initiation IV. Structure of the GR Protein V. GR Mutations and Polymorphisms VI. Post-translational Modifications of the GR Protein A. Phosphorylation B. Ubiquitination C. SUMOylation D. Acetylation E. Nitrosylation F. Oxidation VII. Role for DNA Binding Sequences in Directing GR Conformation and Function VIII. Future Perspectives and Therapeutic Implications I. Introduction G lucocorticoids (GCs) are steroid hormones that are produced by the adrenal cortex, under tight regulation by the hypothalamic-pituitary-adrenal gland axis.